9:6 489–497 L V Larsen et al. PHPT as first manifestation of MEN 2A RESEARCH Primary hyperparathyroidism as first manifestation in multiple endocrine neoplasia type 2A: an international multicenter study Louise Vølund Larsen 1 , Delphine Mirebeau-Prunier 2 , Tsuneo Imai 3 , Cristina Alvarez-Escola 4 , Kornelia Hasse-Lazar 5 , Simona Censi 6 , Luciana A Castroneves 7 , Akihiro Sakurai 8 , Minoru Kihara 9 , Kiyomi Horiuchi 10 , Véronique Dorine Barbu 11,12 , Francoise Borson-Chazot 12,13 , Anne-Paule Gimenez-Roqueplo 12,14,15 , Pascal Pigny 12,16 , Stephane Pinson 12,17 , Nelson Wohllk 18 , Charis Eng 19 , Berna Imge Aydogan 20 , Dhananjaya Saranath 21 , Sarka Dvorakova 22 , Frederic Castinetti 23,24 , Attila Patocs 25 , Damijan Bergant 26 , Thera P Links 27 , Mariola Peczkowska 28 , Ana O Hoff 7 , Caterina Mian 6 , Trisha Dwight 29 , Barbara Jarzab 30 , Hartmut P H Neumann 31 , Mercedes Robledo 32,33 , Shinya Uchino 34 , Anne Barlier 12,35 , Christian Godballe 1 and Jes Sloth Mathiesen 1,36 1 Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark 2 Laboratoire de Biochimie et Biologie Moléculaire, CHU Angers, Université d’Angers, UMR CNRS 6015, INSERM U1083, MITOVASC, Angers, France 3 Department of Breast & Endocrine Surgery, National Hospital Organization, Higashinagoya National Hospital, Nagoya, Japan 4 Endocrinology and Nutrition Department, University Hospital ‘La Paz’, Madrid, Spain 5 Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland 6 Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy 7 Department of Endocrinology, Endocrine Oncology Unit, Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil 8 Department of Medical Genetics and Genomics, Sapporo Medical University School of Medicine, Sapporo, Japan 9 Department of Surgery, Kuma Hospital, Kobe, Hyogo, Japan 10 Department of Breast and Endocrine Surgery, Tokyo Women’s Medical University, Tokyo, Japan 11 AP-HP, Sorbonne Université, Laboratoire Commun de Biologie et Génétique Moléculaires, Hôpital St Antoine & INSERM CRSA, Paris, France 12 Réseau TenGen, Marseille, France 13 Fédération d’Endocrinologie, Hospices Civils de Lyon, Université Lyon 1, France 14 Service de Génétique, AP-HP, Hôpital européen Georges Pompidou, Paris, France 15 Université de Paris, PARCC, INSERM, Paris, France 16 Laboratoire de Biochimie et Oncologie Moléculaire, CHU Lille, Lille, France 17 Laboratoire de Génétique Moléculaire, CHU Lyon, Lyon, France 18 Endocrine Section, Hospital del Salvador, Santiago de Chile, Department of Medicine, University of Chile, Santiago, Chile 19 Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA 20 Department of Endocrinology And Metabolic Diseases, Ankara University School of Medicine, Ankara, Turkey 21 Department of Research Studies & Additional Projects, Cancer Patients Aid Association, Dr. Vithaldas Parmar Research & Medical Centre, Worli, Mumbai, India 22 Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic 23 Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France 24 Department of Endocrinology, Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de Référence des Maladies Rares de l’hypophyse HYPO, Marseille, France 25 HAS-SE Momentum Hereditary Endocrine Tumors Research Group, Semmelweis University, Budapest, Hungary 26 Department of Surgical Oncology, Institute of Oncology, Ljubljana, Slovenia 27 Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands 28 Department of Hypertension, Institute of Cardiology, Warsaw, Poland 29 Cancer Genetics, Kolling Institute, Royal North Shore Hospital and University of Sydney, Sydney, New South Wales, Australia 30 Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland 31 Section for Preventive Medicine, Medical Center-University of Freiburg, Faculty of Medicine, Albert Ludwigs-University of Freiburg, Freiburg, Germany 32 Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain 33 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain 34 Department of Endocrine Surgery, Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Oita, Japan 35 Aix Marseille Univ, APHM, INSERM, MMG, Laboratory of Molecular Biology, Hospital La Conception, Marseille, France 36 Department of Clinical Research, University of Southern Denmark, Odense, Denmark Correspondence should be addressed to J S Mathiesen: [email protected] This work is licensed under a Creative Commons Attribution 4.0 International License. https://doi.org/10.1530/EC-20-0163 https://ec.bioscientifica.com © 2020 The authors Published by Bioscientifica Ltd Downloaded from Bioscientifica.com at 11/05/2020 06:04:05PM niversidade de Sao Paulo, Usp - Biblioteca do Inst de, FMVZ - Faculade de Medicina, Universiadade de Sao Paulo, Universidade de Sao Paulo, Universidade de Sao Paulo and FT USP - UNIVERSIDADE DE SÃO PAULO
Primary hyperparathyroidism as first manifestation in multiple endocrine neoplasia type 2A: an international multicenter study
Dec 26, 2022
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
9:6 489–497L V Larsen et al. PHPT as first manifestation of MEN 2A
RESEARCH
1Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark 2Laboratoire de Biochimie et Biologie Moléculaire, CHU Angers, Université d’Angers, UMR CNRS 6015, INSERM U1083, MITOVASC, Angers, France 3Department of Breast & Endocrine Surgery, National Hospital Organization, Higashinagoya National Hospital, Nagoya, Japan 4Endocrinology and Nutrition Department, University Hospital ‘La Paz’, Madrid, Spain 5Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland 6Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy 7Department of Endocrinology, Endocrine Oncology Unit, Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil 8Department of Medical Genetics and Genomics, Sapporo Medical University School of Medicine, Sapporo, Japan 9Department of Surgery, Kuma Hospital, Kobe, Hyogo, Japan 10Department of Breast and Endocrine Surgery, Tokyo Women’s Medical University, Tokyo, Japan 11AP-HP, Sorbonne Université, Laboratoire Commun de Biologie et Génétique Moléculaires, Hôpital St Antoine & INSERM CRSA, Paris, France 12Réseau TenGen, Marseille, France 13Fédération d’Endocrinologie, Hospices Civils de Lyon, Université Lyon 1, France 14Service de Génétique, AP-HP, Hôpital européen Georges Pompidou, Paris, France 15Université de Paris, PARCC, INSERM, Paris, France 16Laboratoire de Biochimie et Oncologie Moléculaire, CHU Lille, Lille, France 17Laboratoire de Génétique Moléculaire, CHU Lyon, Lyon, France 18Endocrine Section, Hospital del Salvador, Santiago de Chile, Department of Medicine, University of Chile, Santiago, Chile 19Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA 20Department of Endocrinology And Metabolic Diseases, Ankara University School of Medicine, Ankara, Turkey 21Department of Research Studies & Additional Projects, Cancer Patients Aid Association, Dr. Vithaldas Parmar Research & Medical Centre, Worli, Mumbai, India 22Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic 23Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France 24Department of Endocrinology, Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de Référence des Maladies Rares de l’hypophyse HYPO, Marseille, France 25HAS-SE Momentum Hereditary Endocrine Tumors Research Group, Semmelweis University, Budapest, Hungary 26Department of Surgical Oncology, Institute of Oncology, Ljubljana, Slovenia 27Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands 28Department of Hypertension, Institute of Cardiology, Warsaw, Poland 29Cancer Genetics, Kolling Institute, Royal North Shore Hospital and University of Sydney, Sydney, New South Wales, Australia 30Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland 31Section for Preventive Medicine, Medical Center-University of Freiburg, Faculty of Medicine, Albert Ludwigs-University of Freiburg, Freiburg, Germany 32Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain 33Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain 34Department of Endocrine Surgery, Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Oita, Japan 35Aix Marseille Univ, APHM, INSERM, MMG, Laboratory of Molecular Biology, Hospital La Conception, Marseille, France 36Department of Clinical Research, University of Southern Denmark, Odense, Denmark
Correspondence should be addressed to J S Mathiesen: [email protected]
-20-0163
ID: 20-0163 9 6
This work is licensed under a Creative Commons Attribution 4.0 International License.https://doi.org/10.1530/EC-20-0163
https://ec.bioscientifica.com © 2020 The authors Published by Bioscientifica Ltd
Downloaded from Bioscientifica.com at 11/05/2020 06:04:05PM via Universidade de Sao Paulo - Usp, Universidade de Sao Paulo, Universidade de Sao Paulo, Usp - Biblioteca do Inst de, FMVZ - Faculade de Medicina, Universiadade de Sao Paulo, Universidade de Sao Paulo, Universidade de Sao Paulo and FT USP - UNIVERSIDADE DE SÃO PAULO
490
9:6
Abstract
Objective: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations and has been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases. Design and methods: An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centers all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017. Results: Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI: 0.4–1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis. Conclusions: Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation have synchronous MTC and are often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false-negative rate, if no other MEN 2A component, specifically MTC, are found during work-up or resection of PHPT.
Introduction
Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited cancer syndrome caused by germline mutations of the rearranged during transfection (RET) proto-oncogene (1, 2, 3, 4, 5, 6). The syndrome is divided into MEN 2A and MEN 2B with a point prevalence of 13–24 per million and 1–2 per million, respectively (7, 8, 9, 10). Virtually all patients with MEN 2A develop medullary thyroid carcinoma (MTC), while lower numbers develop pheochromocytoma, primary hyperparathyroidism (PHPT), cutaneous lichen amyloidosis (CLA) and Hirschsprung disease (HSCR) (11).
For identification of new MEN 2A index cases and families, RET screening has been recommended for years in all patients with apparently sporadic MTC, pheochromocytoma, CLA and infants with HSCR (11, 12, 13, 14). However, for patients with apparently sporadic PHPT, recommendations on RET screening are less clear. Thus, in 2001 the consensus guidelines from the seventh international workshop on MEN recommended against RET screening in these patients (13), while the issue lacks mentioning in the 2009 and 2015 guidelines by the American Thyroid Association (11, 12).
To ascertain if all patients with apparently sporadic PHPT should be RET screened, a valuable estimate would
be the prevalence of MEN 2A index cases presenting with PHPT as first manifestation in an unselected population- based cohort of apparently sporadic PHPT cases, who have all been RET screened. To our knowledge, however, no such cohorts exist. Instead, a surrogate cohort study is to examine the prevalence of MEN 2A index cases presenting with PHPT as the first manifestation in an unselected cohort of MEN 2A index cases. Based on the experience from previous MEN 2A PHPT series (15, 16), we hypothesized that this prevalence would be low.
Consequently, we aimed to estimate the prevalence of MEN 2A index cases presenting with PHPT as first manifestation in an unselected cohort of MEN 2A index cases. Additionally, we aimed to characterize the cases presenting with PHPT as their first manifestation.
Methods
Study design and participants
This investigation is an international retrospective multicenter study of 1085 MEN 2A index cases. We invited experts from 40 MEN 2 centers all over the world to participate. This yielded a total of 19 centers in
Endocrine Connections
f RET
f pheochromocytoma
This work is licensed under a Creative Commons Attribution 4.0 International License.https://doi.org/10.1530/EC-20-0163
https://ec.bioscientifica.com © 2020 The authors Published by Bioscientifica Ltd
Downloaded from Bioscientifica.com at 11/05/2020 06:04:05PM via Universidade de Sao Paulo - Usp, Universidade de Sao Paulo, Universidade de Sao Paulo, Usp - Biblioteca do Inst de, FMVZ - Faculade de Medicina, Universiadade de Sao Paulo, Universidade de Sao Paulo, Universidade de Sao Paulo and FT USP - UNIVERSIDADE DE SÃO PAULO
4919:6
17 different countries, including Denmark, providing data of index cases followed from 1974 to 2017 (Supplementary Table 1, see section on supplementary materials given at the end of this article). Data were retrieved from June 2017 to September 2019.
Data sources
Data were drawn from the registry of each center. Some of the patients have been reported on previous occasions and updated data were obtained (17, 18, 19, 20, 21, 22, 23, 24, 25, 26).
Variables
Patients were defined as having MEN 2 if they had tested positive for a RET germline sequence change classified as pathogenic (mutation) in the ARUP MEN 2 database on February 1, 2020 (27). For inclusion of only the MEN 2A patients, we excluded those with mutations pathognomonic of MEN 2B (RET M918T and A883F) (28, 29). An index case was defined as a clinically affected individual through whom attention is first drawn to MEN 2A in a family (https://www.cancer.gov/publications/ dictionaries/genetics-dictionary/def/index-case). The first manifestation in MEN 2A was defined by the symptoms or biochemistry leading to initial endocrine work-up and was judged by the MEN 2 experts participating in the study. PHPT had to be both biochemically (hypercalcemia and an elevated or inappropriately normal parathyroid hormone level (30)) and histologically proven, while MTC, pheochromocytoma, CLA and HSCR were considered by histology only. TNM staging was performed according to the seventh edition of the American Joint Committee on Cancer Staging Manual (31). Biochemical cure was regarded as undetectable basal calcitonin at last biochemical follow-up.
Statistical analysis
Continuous data were presented as median and range. All analyses were done using Stata® 15.1 (StataCorp LP).
Ethics
Informed consent was given by all patients participating in the study for RET screening. Ethical approval was obtained from the institutional review boards of all participating centers when required: French National Commission for Computerized Data and Individual
Freedom, Institutional Ethical Review Board of Shinshu University School of Medicine (Matsumoto, Japan), Comité de bioética y bienestar animal of the Instituto de Salud Carlos III, Northern Sydney Local Health District Human Research Ethics Committee, ICESP/HCFMUSP, Ethics Committee of the Institute of Cardiology (Warsaw, Poland), Regional Committee on Health Research Ethics for Southern Denmark, Scientific and Research Committee of the Medical Research Council of Hungary, Ethics Committee of Aix Marseille University, Ethics Committee of the Institute of Endocrinology (Prague, Czech Republic), Ethics Committee of Reliance Life Sciences (Navi Mumbai, India), Local Ethics Committee of Ankara University Faculty of Medicine, Cleveland Clinic Institutional Review Board for Human Subjects Protection and Ethical Committee (Santiago, Chile). This was in accordance with the ethical standards of each country and center.
The investigation was approved by the respective institutional review boards for human subjects protection in accordance with the ethical standards of each country and center.
Results
A total of 1085 MEN 2A index cases were included in the study. The distribution of RET germline mutations in these cases is shown in Table 1. The most frequent site of mutations was exon 11 (53%), followed by exon 10 (25%), exon 14 (12%), exon 13 (7%), exon 15 (3%), exon 8 (1%) and exon 16 (0%). Of the 1085 cases, 10 had presented with PHPT as first manifestation of the syndrome, yielding a prevalence of 0.9% (95% CI: 0.4–1.6).
Characteristics of the ten cases are depicted in Table 2. In these cases, the female-to-male ratio was 4.0 (95% CI: −2.2–10.2), while the median age at diagnosis of PHPT was 34.5 years (range, 14–68). All cases were diagnosed with PHPT between 1993 and 2012. Of these, seven were diagnosed in the new millennium.
All cases with pertinent data (n = 9) were symptomatic at diagnosis of PHPT with symptoms being nephrolithiasis (n = 8) and polyuria (n = 1). MTC was diagnosed in 10/10 cases. 9/10 were diagnosed in relation to parathyroid surgery as a synchronous MTC and 1/10 was diagnosed 15 years after parathyroid surgery, as a metachronous MTC. In three cases, MTC was not suspected during preoperative PHPT work-up, but diagnosed during parathyroid surgery. 7/9 cases with full TNM data available had regional lymph node metastases at time of
This work is licensed under a Creative Commons Attribution 4.0 International License.https://doi.org/10.1530/EC-20-0163
https://ec.bioscientifica.com © 2020 The authors Published by Bioscientifica Ltd
Downloaded from Bioscientifica.com at 11/05/2020 06:04:05PM via Universidade de Sao Paulo - Usp, Universidade de Sao Paulo, Universidade de Sao Paulo, Usp - Biblioteca do Inst de, FMVZ - Faculade de Medicina, Universiadade de Sao Paulo, Universidade de Sao Paulo, Universidade de Sao Paulo and FT USP - UNIVERSIDADE DE SÃO PAULO
492
9:6
MTC diagnosis. Biochemical cure was achieved only in the node-negative cases (n = 2).
Discussion
This large international retrospective multicenter study found that 0.9% of cases had PHPT as their first manifestation of MEN 2A. In the cases presenting with PHPT as first manifestation, MTC was coexistent and had metastasized to regional lymph nodes in 7/9 cases.
Prevalence
In this study, we found 0.9% of our MEN 2A index cases presented with PHPT as the first manifestation of the syndrome. To our knowledge, no similar studies on MEN 2A index cases have been reported, rendering comparisons difficult. However, there exist several studies, in which the study cohorts comprise only MEN 2A cases with PHPT. In these cohorts the prevalence of MEN 2A cases presenting with PHPT as a first manifestation ranges 0–11%
(15, 16, 32, 33, 34, 35). Considering the selection of these cohorts and the fact that they included index and non-index cases, presumably a majority of the latter, our prevalence of 0.9% appears as a solid estimate. This is in line with the experience of other smaller series, that PHPT rarely was the first diagnosed manifestation (16, 36). In fact, there seems to be a decrease in the overall prevalence of PHPT in MEN 2A cohorts reported over time, possibly explained by inclusion of more patients with the full- blown syndrome (MTC, pheochromocytoma and PHPT) in the earliest series (6, 33, 37).
In our overall cohort, the most frequently mutated codon was 634, followed by codons 804, 618, 620, 790, 611, 891, 609, 768 and other rarely mutated codons. With only minor differences, likely accounted for by founder effects, the distribution of mutations in our cohort is, by and large, comparable to that of series in the literature (7, 17, 19, 20, 21, 38, 39, 40, 41, 42, 43, 44, 45).
Characteristics of cases
Our study depicts the characteristics of MEN 2A index cases presenting with PHPT as first manifestation. Age at diagnosis is by and large similar to that of other MEN 2A PHPT cohorts (15, 16, 32, 33, 35, 46). Our female-to- male ratio of 4.0 is higher than that (1.3–1.9) reported by others (15, 16, 32, 34). This may be a question of sample size, but may also indicate that female MEN 2A cases in comparison to males are more prone to present with PHPT as first manifestation.
In our cohort all cases with pertinent data were symptomatic at diagnosis of PHPT. This is in contrast with other MEN 2A PHPT cohorts, in which most cases (58–84%) are asymptomatic (15, 16, 32, 33, 34). A likely explanation is the difference in cohorts, where our cohort solely comprises index cases presenting with PHPT as first manifestation, while the other cohorts presumably comprise mainly non-index cases diagnosed with PHPT by screening before they become symptomatic.
Nine of our ten cases were diagnosed with MTC, either due to a suspected or unsuspected finding in relation to parathyroid surgery. As a consequence, RET screening would be prompted by the MTC, if not instigated by the PHPT diagnosis. To our knowledge, the MTC TNM stage of the cases has not previously been reported in MEN 2A PHPT cohorts. In our cohort, 7/9 cases with available data were MTC node positive. This may reflect an over- representation of codon 634 mutation carriers (6/10), who generally have earlier age at MTC onset compared with other MEN 2A patients (47, 48). The over-representation
Table 1 Distributions of RET mutations among 1085 MEN 2A index cases.
RET mutation n (%)
Exon 8 C531R 3 (0) G533C 5 (0) G548S 2 (0) Exon 10 C609F/G/R/S/Y 19 (2) C611F/G/W/Y 48 (4) C618F/G/R/S/W/Y 113 (10) C620F/G/R/S/W/Y 87 (8) Exon 11 C630R/Y 4 (0) D631Y 3 (0) C634F/G/L/S/R/W/Y 562 (52) K666E/N/T 6 (1) Exon 13 E768D 18 (2) Q781R 1 (0) L790F 52 (5) Exon 14 V804L/M 132 (12) Exon 15 S891A 28 (3) Exon 16 R912P 1 (0) M918V 1 (0) Total 1085 (100)
Due to rounding up, not all sums of the numbers fit. MEN 2A, multiple endocrine neoplasia type 2A; RET, rearranged during transfection.
This work is licensed under a Creative Commons Attribution 4.0 International License.https://doi.org/10.1530/EC-20-0163
https://ec.bioscientifica.com © 2020 The authors Published by Bioscientifica Ltd
Downloaded from Bioscientifica.com at 11/05/2020 06:04:05PM via Universidade de Sao Paulo - Usp, Universidade de Sao Paulo, Universidade de Sao Paulo, Usp - Biblioteca do Inst de, FMVZ - Faculade de Medicina, Universiadade de Sao Paulo, Universidade de Sao Paulo, Universidade de Sao Paulo and FT USP - UNIVERSIDADE DE SÃO PAULO
4939:6
in this cohort of MEN2A index cases presenting with PHPT as first manifestation is expected, as carriers of codon 634 mutations are regarded as having the highest penetrance of PHPT (6, 46). Given the fact, that long- term biochemical cure only rarely occurs in node-positive MTC (49), the likelihood of cure as indicated by our cohort is supposedly very low for MEN 2A index cases that present with PHPT as their first manifestation. Due to the high prevalence of regional lymph node metastases in these cases, neck dissection is often warranted already at primary surgery for better local control. Although controversial, the preoperative serum calcitonin level may also guide this decision, despite the fact that high levels not always guarantee metastases (50, 51, 52). On a general comment, the cohort of cases presenting with PHPT as first manifestation is small making generalizations difficult.
Limitations
To assess if all cases with apparently sporadic PHPT should be RET screened, one could have estimated the prevalence of MEN 2A index cases presenting with PHPT as first manifestation in an unselected population-based cohort of cases with apparently sporadic PHPT, in which all had been RET screened. To our knowledge, no such cohorts exist, rendering such a study unfeasible. Instead, we sought to estimate the prevalence of MEN 2A index cases presenting with PHPT as their first manifestation in the largest series of MEN 2A index cases seen to date.
An issue that may underestimate the prevalence is the fact that our study cohort consists of already recognized MEN 2A index cases. Thus, we cannot rule out that some MEN 2A index cases presenting with PHPT as first manifestation, are still unrecognized as MEN 2A cases, if they have not been RET screened and instead are still regarded as sporadic PHPT cases. To comply with this, a study cohort of apparently sporadic PHPT cases is needed as previously described. However, as the first RET germline mutations causing MEN 2A were discovered >25 years ago (1, 2) combined with the fact that de novo mutations rarely occur (53), one may argue that the pool of unrecognized MEN 2A families arising from de novo mutations likely is very small, thus minimizing the issue.
As in several other multicenter studies on MEN 2, selection bias in the current study cannot be ruled out (6, 15, 28, 29, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63). Including all MEN 2 centers in the world is an immensely difficult and time-consuming task. However, formation of a consortium including all MEN 2 centers worldwide may be helpful for future studies.Ta
bl e
2 Ch
ar ac
te ri
st ic
s of
M EN
2 A
in de
x ca
se s
pr es
en tin
g w
ith P
H PT
a s
fir st
m an
ife st
at io
es .
This work is licensed under a Creative Commons Attribution 4.0 International License.https://doi.org/10.1530/EC-20-0163
https://ec.bioscientifica.com ©…
RESEARCH
1Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark 2Laboratoire de Biochimie et Biologie Moléculaire, CHU Angers, Université d’Angers, UMR CNRS 6015, INSERM U1083, MITOVASC, Angers, France 3Department of Breast & Endocrine Surgery, National Hospital Organization, Higashinagoya National Hospital, Nagoya, Japan 4Endocrinology and Nutrition Department, University Hospital ‘La Paz’, Madrid, Spain 5Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland 6Endocrinology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy 7Department of Endocrinology, Endocrine Oncology Unit, Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil 8Department of Medical Genetics and Genomics, Sapporo Medical University School of Medicine, Sapporo, Japan 9Department of Surgery, Kuma Hospital, Kobe, Hyogo, Japan 10Department of Breast and Endocrine Surgery, Tokyo Women’s Medical University, Tokyo, Japan 11AP-HP, Sorbonne Université, Laboratoire Commun de Biologie et Génétique Moléculaires, Hôpital St Antoine & INSERM CRSA, Paris, France 12Réseau TenGen, Marseille, France 13Fédération d’Endocrinologie, Hospices Civils de Lyon, Université Lyon 1, France 14Service de Génétique, AP-HP, Hôpital européen Georges Pompidou, Paris, France 15Université de Paris, PARCC, INSERM, Paris, France 16Laboratoire de Biochimie et Oncologie Moléculaire, CHU Lille, Lille, France 17Laboratoire de Génétique Moléculaire, CHU Lyon, Lyon, France 18Endocrine Section, Hospital del Salvador, Santiago de Chile, Department of Medicine, University of Chile, Santiago, Chile 19Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA 20Department of Endocrinology And Metabolic Diseases, Ankara University School of Medicine, Ankara, Turkey 21Department of Research Studies & Additional Projects, Cancer Patients Aid Association, Dr. Vithaldas Parmar Research & Medical Centre, Worli, Mumbai, India 22Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic 23Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France 24Department of Endocrinology, Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de Référence des Maladies Rares de l’hypophyse HYPO, Marseille, France 25HAS-SE Momentum Hereditary Endocrine Tumors Research Group, Semmelweis University, Budapest, Hungary 26Department of Surgical Oncology, Institute of Oncology, Ljubljana, Slovenia 27Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands 28Department of Hypertension, Institute of Cardiology, Warsaw, Poland 29Cancer Genetics, Kolling Institute, Royal North Shore Hospital and University of Sydney, Sydney, New South Wales, Australia 30Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland 31Section for Preventive Medicine, Medical Center-University of Freiburg, Faculty of Medicine, Albert Ludwigs-University of Freiburg, Freiburg, Germany 32Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain 33Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain 34Department of Endocrine Surgery, Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Oita, Japan 35Aix Marseille Univ, APHM, INSERM, MMG, Laboratory of Molecular Biology, Hospital La Conception, Marseille, France 36Department of Clinical Research, University of Southern Denmark, Odense, Denmark
Correspondence should be addressed to J S Mathiesen: [email protected]
-20-0163
ID: 20-0163 9 6
This work is licensed under a Creative Commons Attribution 4.0 International License.https://doi.org/10.1530/EC-20-0163
https://ec.bioscientifica.com © 2020 The authors Published by Bioscientifica Ltd
Downloaded from Bioscientifica.com at 11/05/2020 06:04:05PM via Universidade de Sao Paulo - Usp, Universidade de Sao Paulo, Universidade de Sao Paulo, Usp - Biblioteca do Inst de, FMVZ - Faculade de Medicina, Universiadade de Sao Paulo, Universidade de Sao Paulo, Universidade de Sao Paulo and FT USP - UNIVERSIDADE DE SÃO PAULO
490
9:6
Abstract
Objective: Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations and has been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases. Design and methods: An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centers all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017. Results: Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI: 0.4–1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis. Conclusions: Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation have synchronous MTC and are often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false-negative rate, if no other MEN 2A component, specifically MTC, are found during work-up or resection of PHPT.
Introduction
Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant inherited cancer syndrome caused by germline mutations of the rearranged during transfection (RET) proto-oncogene (1, 2, 3, 4, 5, 6). The syndrome is divided into MEN 2A and MEN 2B with a point prevalence of 13–24 per million and 1–2 per million, respectively (7, 8, 9, 10). Virtually all patients with MEN 2A develop medullary thyroid carcinoma (MTC), while lower numbers develop pheochromocytoma, primary hyperparathyroidism (PHPT), cutaneous lichen amyloidosis (CLA) and Hirschsprung disease (HSCR) (11).
For identification of new MEN 2A index cases and families, RET screening has been recommended for years in all patients with apparently sporadic MTC, pheochromocytoma, CLA and infants with HSCR (11, 12, 13, 14). However, for patients with apparently sporadic PHPT, recommendations on RET screening are less clear. Thus, in 2001 the consensus guidelines from the seventh international workshop on MEN recommended against RET screening in these patients (13), while the issue lacks mentioning in the 2009 and 2015 guidelines by the American Thyroid Association (11, 12).
To ascertain if all patients with apparently sporadic PHPT should be RET screened, a valuable estimate would
be the prevalence of MEN 2A index cases presenting with PHPT as first manifestation in an unselected population- based cohort of apparently sporadic PHPT cases, who have all been RET screened. To our knowledge, however, no such cohorts exist. Instead, a surrogate cohort study is to examine the prevalence of MEN 2A index cases presenting with PHPT as the first manifestation in an unselected cohort of MEN 2A index cases. Based on the experience from previous MEN 2A PHPT series (15, 16), we hypothesized that this prevalence would be low.
Consequently, we aimed to estimate the prevalence of MEN 2A index cases presenting with PHPT as first manifestation in an unselected cohort of MEN 2A index cases. Additionally, we aimed to characterize the cases presenting with PHPT as their first manifestation.
Methods
Study design and participants
This investigation is an international retrospective multicenter study of 1085 MEN 2A index cases. We invited experts from 40 MEN 2 centers all over the world to participate. This yielded a total of 19 centers in
Endocrine Connections
f RET
f pheochromocytoma
This work is licensed under a Creative Commons Attribution 4.0 International License.https://doi.org/10.1530/EC-20-0163
https://ec.bioscientifica.com © 2020 The authors Published by Bioscientifica Ltd
Downloaded from Bioscientifica.com at 11/05/2020 06:04:05PM via Universidade de Sao Paulo - Usp, Universidade de Sao Paulo, Universidade de Sao Paulo, Usp - Biblioteca do Inst de, FMVZ - Faculade de Medicina, Universiadade de Sao Paulo, Universidade de Sao Paulo, Universidade de Sao Paulo and FT USP - UNIVERSIDADE DE SÃO PAULO
4919:6
17 different countries, including Denmark, providing data of index cases followed from 1974 to 2017 (Supplementary Table 1, see section on supplementary materials given at the end of this article). Data were retrieved from June 2017 to September 2019.
Data sources
Data were drawn from the registry of each center. Some of the patients have been reported on previous occasions and updated data were obtained (17, 18, 19, 20, 21, 22, 23, 24, 25, 26).
Variables
Patients were defined as having MEN 2 if they had tested positive for a RET germline sequence change classified as pathogenic (mutation) in the ARUP MEN 2 database on February 1, 2020 (27). For inclusion of only the MEN 2A patients, we excluded those with mutations pathognomonic of MEN 2B (RET M918T and A883F) (28, 29). An index case was defined as a clinically affected individual through whom attention is first drawn to MEN 2A in a family (https://www.cancer.gov/publications/ dictionaries/genetics-dictionary/def/index-case). The first manifestation in MEN 2A was defined by the symptoms or biochemistry leading to initial endocrine work-up and was judged by the MEN 2 experts participating in the study. PHPT had to be both biochemically (hypercalcemia and an elevated or inappropriately normal parathyroid hormone level (30)) and histologically proven, while MTC, pheochromocytoma, CLA and HSCR were considered by histology only. TNM staging was performed according to the seventh edition of the American Joint Committee on Cancer Staging Manual (31). Biochemical cure was regarded as undetectable basal calcitonin at last biochemical follow-up.
Statistical analysis
Continuous data were presented as median and range. All analyses were done using Stata® 15.1 (StataCorp LP).
Ethics
Informed consent was given by all patients participating in the study for RET screening. Ethical approval was obtained from the institutional review boards of all participating centers when required: French National Commission for Computerized Data and Individual
Freedom, Institutional Ethical Review Board of Shinshu University School of Medicine (Matsumoto, Japan), Comité de bioética y bienestar animal of the Instituto de Salud Carlos III, Northern Sydney Local Health District Human Research Ethics Committee, ICESP/HCFMUSP, Ethics Committee of the Institute of Cardiology (Warsaw, Poland), Regional Committee on Health Research Ethics for Southern Denmark, Scientific and Research Committee of the Medical Research Council of Hungary, Ethics Committee of Aix Marseille University, Ethics Committee of the Institute of Endocrinology (Prague, Czech Republic), Ethics Committee of Reliance Life Sciences (Navi Mumbai, India), Local Ethics Committee of Ankara University Faculty of Medicine, Cleveland Clinic Institutional Review Board for Human Subjects Protection and Ethical Committee (Santiago, Chile). This was in accordance with the ethical standards of each country and center.
The investigation was approved by the respective institutional review boards for human subjects protection in accordance with the ethical standards of each country and center.
Results
A total of 1085 MEN 2A index cases were included in the study. The distribution of RET germline mutations in these cases is shown in Table 1. The most frequent site of mutations was exon 11 (53%), followed by exon 10 (25%), exon 14 (12%), exon 13 (7%), exon 15 (3%), exon 8 (1%) and exon 16 (0%). Of the 1085 cases, 10 had presented with PHPT as first manifestation of the syndrome, yielding a prevalence of 0.9% (95% CI: 0.4–1.6).
Characteristics of the ten cases are depicted in Table 2. In these cases, the female-to-male ratio was 4.0 (95% CI: −2.2–10.2), while the median age at diagnosis of PHPT was 34.5 years (range, 14–68). All cases were diagnosed with PHPT between 1993 and 2012. Of these, seven were diagnosed in the new millennium.
All cases with pertinent data (n = 9) were symptomatic at diagnosis of PHPT with symptoms being nephrolithiasis (n = 8) and polyuria (n = 1). MTC was diagnosed in 10/10 cases. 9/10 were diagnosed in relation to parathyroid surgery as a synchronous MTC and 1/10 was diagnosed 15 years after parathyroid surgery, as a metachronous MTC. In three cases, MTC was not suspected during preoperative PHPT work-up, but diagnosed during parathyroid surgery. 7/9 cases with full TNM data available had regional lymph node metastases at time of
This work is licensed under a Creative Commons Attribution 4.0 International License.https://doi.org/10.1530/EC-20-0163
https://ec.bioscientifica.com © 2020 The authors Published by Bioscientifica Ltd
Downloaded from Bioscientifica.com at 11/05/2020 06:04:05PM via Universidade de Sao Paulo - Usp, Universidade de Sao Paulo, Universidade de Sao Paulo, Usp - Biblioteca do Inst de, FMVZ - Faculade de Medicina, Universiadade de Sao Paulo, Universidade de Sao Paulo, Universidade de Sao Paulo and FT USP - UNIVERSIDADE DE SÃO PAULO
492
9:6
MTC diagnosis. Biochemical cure was achieved only in the node-negative cases (n = 2).
Discussion
This large international retrospective multicenter study found that 0.9% of cases had PHPT as their first manifestation of MEN 2A. In the cases presenting with PHPT as first manifestation, MTC was coexistent and had metastasized to regional lymph nodes in 7/9 cases.
Prevalence
In this study, we found 0.9% of our MEN 2A index cases presented with PHPT as the first manifestation of the syndrome. To our knowledge, no similar studies on MEN 2A index cases have been reported, rendering comparisons difficult. However, there exist several studies, in which the study cohorts comprise only MEN 2A cases with PHPT. In these cohorts the prevalence of MEN 2A cases presenting with PHPT as a first manifestation ranges 0–11%
(15, 16, 32, 33, 34, 35). Considering the selection of these cohorts and the fact that they included index and non-index cases, presumably a majority of the latter, our prevalence of 0.9% appears as a solid estimate. This is in line with the experience of other smaller series, that PHPT rarely was the first diagnosed manifestation (16, 36). In fact, there seems to be a decrease in the overall prevalence of PHPT in MEN 2A cohorts reported over time, possibly explained by inclusion of more patients with the full- blown syndrome (MTC, pheochromocytoma and PHPT) in the earliest series (6, 33, 37).
In our overall cohort, the most frequently mutated codon was 634, followed by codons 804, 618, 620, 790, 611, 891, 609, 768 and other rarely mutated codons. With only minor differences, likely accounted for by founder effects, the distribution of mutations in our cohort is, by and large, comparable to that of series in the literature (7, 17, 19, 20, 21, 38, 39, 40, 41, 42, 43, 44, 45).
Characteristics of cases
Our study depicts the characteristics of MEN 2A index cases presenting with PHPT as first manifestation. Age at diagnosis is by and large similar to that of other MEN 2A PHPT cohorts (15, 16, 32, 33, 35, 46). Our female-to- male ratio of 4.0 is higher than that (1.3–1.9) reported by others (15, 16, 32, 34). This may be a question of sample size, but may also indicate that female MEN 2A cases in comparison to males are more prone to present with PHPT as first manifestation.
In our cohort all cases with pertinent data were symptomatic at diagnosis of PHPT. This is in contrast with other MEN 2A PHPT cohorts, in which most cases (58–84%) are asymptomatic (15, 16, 32, 33, 34). A likely explanation is the difference in cohorts, where our cohort solely comprises index cases presenting with PHPT as first manifestation, while the other cohorts presumably comprise mainly non-index cases diagnosed with PHPT by screening before they become symptomatic.
Nine of our ten cases were diagnosed with MTC, either due to a suspected or unsuspected finding in relation to parathyroid surgery. As a consequence, RET screening would be prompted by the MTC, if not instigated by the PHPT diagnosis. To our knowledge, the MTC TNM stage of the cases has not previously been reported in MEN 2A PHPT cohorts. In our cohort, 7/9 cases with available data were MTC node positive. This may reflect an over- representation of codon 634 mutation carriers (6/10), who generally have earlier age at MTC onset compared with other MEN 2A patients (47, 48). The over-representation
Table 1 Distributions of RET mutations among 1085 MEN 2A index cases.
RET mutation n (%)
Exon 8 C531R 3 (0) G533C 5 (0) G548S 2 (0) Exon 10 C609F/G/R/S/Y 19 (2) C611F/G/W/Y 48 (4) C618F/G/R/S/W/Y 113 (10) C620F/G/R/S/W/Y 87 (8) Exon 11 C630R/Y 4 (0) D631Y 3 (0) C634F/G/L/S/R/W/Y 562 (52) K666E/N/T 6 (1) Exon 13 E768D 18 (2) Q781R 1 (0) L790F 52 (5) Exon 14 V804L/M 132 (12) Exon 15 S891A 28 (3) Exon 16 R912P 1 (0) M918V 1 (0) Total 1085 (100)
Due to rounding up, not all sums of the numbers fit. MEN 2A, multiple endocrine neoplasia type 2A; RET, rearranged during transfection.
This work is licensed under a Creative Commons Attribution 4.0 International License.https://doi.org/10.1530/EC-20-0163
https://ec.bioscientifica.com © 2020 The authors Published by Bioscientifica Ltd
Downloaded from Bioscientifica.com at 11/05/2020 06:04:05PM via Universidade de Sao Paulo - Usp, Universidade de Sao Paulo, Universidade de Sao Paulo, Usp - Biblioteca do Inst de, FMVZ - Faculade de Medicina, Universiadade de Sao Paulo, Universidade de Sao Paulo, Universidade de Sao Paulo and FT USP - UNIVERSIDADE DE SÃO PAULO
4939:6
in this cohort of MEN2A index cases presenting with PHPT as first manifestation is expected, as carriers of codon 634 mutations are regarded as having the highest penetrance of PHPT (6, 46). Given the fact, that long- term biochemical cure only rarely occurs in node-positive MTC (49), the likelihood of cure as indicated by our cohort is supposedly very low for MEN 2A index cases that present with PHPT as their first manifestation. Due to the high prevalence of regional lymph node metastases in these cases, neck dissection is often warranted already at primary surgery for better local control. Although controversial, the preoperative serum calcitonin level may also guide this decision, despite the fact that high levels not always guarantee metastases (50, 51, 52). On a general comment, the cohort of cases presenting with PHPT as first manifestation is small making generalizations difficult.
Limitations
To assess if all cases with apparently sporadic PHPT should be RET screened, one could have estimated the prevalence of MEN 2A index cases presenting with PHPT as first manifestation in an unselected population-based cohort of cases with apparently sporadic PHPT, in which all had been RET screened. To our knowledge, no such cohorts exist, rendering such a study unfeasible. Instead, we sought to estimate the prevalence of MEN 2A index cases presenting with PHPT as their first manifestation in the largest series of MEN 2A index cases seen to date.
An issue that may underestimate the prevalence is the fact that our study cohort consists of already recognized MEN 2A index cases. Thus, we cannot rule out that some MEN 2A index cases presenting with PHPT as first manifestation, are still unrecognized as MEN 2A cases, if they have not been RET screened and instead are still regarded as sporadic PHPT cases. To comply with this, a study cohort of apparently sporadic PHPT cases is needed as previously described. However, as the first RET germline mutations causing MEN 2A were discovered >25 years ago (1, 2) combined with the fact that de novo mutations rarely occur (53), one may argue that the pool of unrecognized MEN 2A families arising from de novo mutations likely is very small, thus minimizing the issue.
As in several other multicenter studies on MEN 2, selection bias in the current study cannot be ruled out (6, 15, 28, 29, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63). Including all MEN 2 centers in the world is an immensely difficult and time-consuming task. However, formation of a consortium including all MEN 2 centers worldwide may be helpful for future studies.Ta
bl e
2 Ch
ar ac
te ri
st ic
s of
M EN
2 A
in de
x ca
se s
pr es
en tin
g w
ith P
H PT
a s
fir st
m an
ife st
at io
es .
This work is licensed under a Creative Commons Attribution 4.0 International License.https://doi.org/10.1530/EC-20-0163
https://ec.bioscientifica.com ©…
Related Documents
